Histone Deacetylase Inhibitors In Cancer Cells Research Articles

Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells.

Period circadian regulator (Per)1 and Per2 genes are involved in the molecular mechanism of the circadian clock, and exhibit tumor suppressor properties. Several studies have reported a decreased expression of Per1, Per2 and Per3 genes in different types of cancer and cancer cell lines. Promoter methylation downregulates Per1, Per2 or Per3 expression in myeloid leukemia, breast, lung, and other cancer cells; whereas histone deacetylase inhibitors (HDACi) upregulate Per1 or Per3 expression in certain cancer cell lines. However, the transcriptional regulation of Per1 and Per2 in cancer cells by chromatin modifications is not fully understood. The present study aimed to determine whether HDACi regulate Per1 and Per2 expression in gastric cancer cell lines, and to investigate changes in chromatin modifications in response to HDACi. Treatment of KATO III and NCI-N87 human gastric cancer cells with sodium butyrate (NaB) or Trichostatin A (TSA) induced Per1 and Per2 mRNA expression in a dose-dependent manner. Chromatin immunoprecipitaion assays revealed that NaB and TSA decreased lysine 9 trimethylation on histone H3 (H3K9me3) at the Per1 promoter. TSA, but not NaB increased H3K9 acetylation at the Per2 promoter. It was also observed that binding of Sp1 and Sp3 to the Per1 promoter decreased following NaB treatment, whereas Sp1 binding increased at the Per2 promoter of NaB- and TSA-treated cells. In addition, Per1 promoter is not methylated in KATO III cells, while Per2 promoter was methylated, although NaB, TSA, and 5-Azacytidine do not change the methylated CpGs analyzed. In conclusion, HDACi induce Per1 and Per2 expression, in part, through mechanisms involving chromatin remodeling at the proximal promoter of these genes; however, other indirect mechanisms triggered by these HDACi cannot be ruled out. These findings reveal a previously unappreciated regulatory pathway between silencing of Per1 gene by H3K9me3 and upregulation of Per2 by HDACi in cancer cells.

Cancer Cells‘ Epigenetic Composition And Predisposition to Histone Deacetylase Inhibitor Sensitization

Normal cells are up to ten times more resistant to histone deacetylase inhibitors (HDACis)-induced cell death compared with transformed cells. The molecular processes underlying this selectivity for cancer cells are still not well understood. Although a differential response to oxidative stress and capacity to repair damaged DNA have been described in some systems, these cannot fully account for the sensitivity of cancer cells to HDACis since the heterogeneity of cancer cells prompts differential sensitivities to reactive oxygen species and generates a panoply of defective DNA repair mechanisms within given histologies, cancer cell lines and tumor xenografts. It seems also unlikely that the influence of HDACis on cancer treatments reside primarily on gene transcription, since gene-expression profiling aimed at defining correlation with response to HDACis in cancer cells indicates that less than 5% to approximately 20% of transcribed genes are altered by HDACis treatment. Moreover, the altered genes vary from cell line to cell line and between different HDACis. Therefore, no consistent picture of a target(s) or pathway(s) modulated by HDACis has emerged. One consistent parameter that has however been observed in peripheral blood mononuclear cells of patients treated with HDACi is the accumulation of acetylated histones. Because one of the primary functions of histone acetylation is to increase chromatin accessibility, this article will explore the possibility that intrinsic molecular and structural characteristics of cancer cells provide a selective advantage for HDACis sensitivity.

Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase

The molecular basis of the antitumor selectivity of histone deacetylase inhibitors (HDIs) remains unclear. Centrosomal Aurora-A kinase regulates chromosomal segregation during mitosis. The overexpression or amplification of Aurora-A leads to genetic instability, and its inhibition has shown significant antitumor effects. In this paper, we report that structurally related hydroxamate LAQ824 and SK-7068 induce tumor-selective mitotic defects by depleting Aurora-A. We found that HDI-treated cancer cells, unlike nontransformed cells, exhibit defective mitotic spindles. After HDI, Aurora-A was selectively downregulated in cancer cells, whereas Aurora-B remained unchanged in both cancer and nontransformed cells. LAQ824 or SK-7068 treatment inhibited histone deacetylase (HDAC) 6 present in Aurora-A/heat shock protein (Hsp) 90 complex. Inhibition of HDAC6 acetylated Hsp90 and resulted in dissociation of acetylated Hsp90 from Aurora-A. As a result, Hsp70 binding to Aurora-A was enhanced in cancer cells, leading to proteasomal degradation of Aurora-A. Overall, these provide a novel molecular basis of tumor selectivity of HDI. LAQ824 and SK-7068 might be more effective HDIs in cancer cells with Aurora-A overexpression.